Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Definitions

• nucleosides Various processes for the preparation of nucleosides are known per se. For example, Y. Furukawa et al in Chem. Pharm. Bull. 16:1067 (1968) described the reaction of purines with 1-O-acyl or 1-O-alkyl derivatives of a sugar in the presence of Friedel-Crafts catalysts to obtain the corresponding N-glycosides.
• German Pat. No. 1,919,307 discloses a process for the production of nucleosides in which silylated N-heterocyclic bases are reacted with masked 1-halo-, 1-O-alkyl-, and especially 1-acyl-sugars in the presence of Friedel-Crafts catalysts.
• Another object of this invention is to provide such a process wherein the formation of unwanted emulsions or colloids is avoided while working-up the reaction mixture.
• a further object of this invention is to provide such a process wherein the product is principally a ⁇ -glycoside obtained in a high yield.
• the trialkylsilyl portion of the ester is one in which the alkyl groups are all lower alkyl of 1-6 carbon atoms, preferably methyl or ethyl and especially methyl.
• the alkyl groups may each be the same or different, although it is preferred that at least one, preferably two and especially all three, alkyl groups are methyl or ethyl.
• Especially suitable are the easily available mono- or polytrimethylsilyl esters, e.g. (CH 3 ) 3 Si--OClO 3 , (CH 3 ) 3 Si--OSO 2 F and (CH 3 ) 3 Si--OCOCF 3 .
• the esterified mineral acid or organic acid is a strong acid, i.e. one having a --H o value of at least 12.00, and is capable of trialkylsilyl ester formation.
• Suitable such acids are well known in the art and include but are not limited to the halogenated per-acids, e.g. perfluoric and perchloric acids; sulfur-containing acids, e.g. fluoro- and chloro- sulfonic acids, sulfuric and sulfonic acids; and strong organic acids, e.g. trifluoromethane sulfonic acid.
• SnCl 4 as catalyst by the trimethylsilyl esters of acids in nucleoside synthesis, different donor acceptor or ⁇ -complexes are formed between the silylated heterocycles as bases or donors and the trimethylsilylesters of strong acids compared to catalysts like SnCl 4 , since SnCl 4 or TiCl 4 have the coordination number of 6 whereas the trimethylsilylesters of strong acids form probably only simple acid-base donor-acceptor complexes.
• the new catalysts give a much higher proportion of the desired N 1 -nucleosides (e.g. examples 7-12) than SnCl 4 or TiCl 4 . Furthermore the adverse formation of emulsions and colloids during the working-up process is avoided and the yields are increased.
• This invention accordingly relates to a process for the preparation of preferably heterocyclic nucleosides by reacting the corresponding silylated, preferably heterocyclic organic nucleoside bases with a 1-O-acyl, 1-O-alkyl or 1-halogen derivative of a masked sugar in the presence of a catalyst, characterized in that trialkylsilyl esters, especially trimethylsilyl esters, of mineral acids or strong organic acids are utilized as the catalyst.
• silylated organic bases useful in nucleoside synthesis are suitable for use with the catalysts of the present invention.
• bases are well known in the art and include but are not limited to organic bases of the Formulae ##STR1## wherein X is oxygen or sulfur;
• n is the number 0 or 1;
• R 1 and R 2 are each a saturated or unsaturated optionally substituted aliphatic, cycloaliphatic or aromatic residue of a nucleoside base, or R 1 and R 2 together represent a bivalent aliphatic residue which can contain one or two nitrogen atoms, and
• R 3 and R 4 are each hydrogen, lower alkyl, lower alkoxycarbonyl or lower alkylaminocarbonyl, or R 3 and R 4 together represent the bivalent residues ##STR2## which can be substituted in the usual manner, and Y is trialkylsilyl of 1-6 carbon atoms in each alkyl group, especially trimethylsilyl.
• R 1 and R 2 as aliphatic are the lower alkyl groups, preferably of 1-4 carbon atoms, i.e. methyl, ethyl, propyl or butyl.
• Preferred values for R 1 and R 2 as aromatic are aryl and aralkyl, e.g. phenyl, benzyl, tolyl, xylyl, etc.
• the bivalent residues R 1 and R 2 or R 3 and R 4 can contain the following substituents, for example: lower alkyl, trifluoromethyl, alkanoyl, hydroxy, alkoxy, alkanoyloxy, carboxyl, carboxamide, alkoxycarbonyl, dialkylaminocarbonyl, amino, nitro, nitriloxo or halogen.
• Preferred starting compounds are those silylated organic bases wherein R 1 and R 2 are linked to a ring, especially in such a way that the heterocyclic bases contain five or six atoms in the ring, and among those one to three nitrogen atoms.
• the silylated organic bases according to Formulae Ia and Ib are preferably derived from the following heterocyclic bases: uracil, cytosine, 6-azauracil, 2-thio-6-azauracil, thymine, N-acetyladenine, guanine, lumazine [2,4(1H,3H) pteridinedione], imidazole, pyrazine, thiazole or triazole, each of which can optionally be substituted by one or more of the aforementioned residues R 1 and R 2 as well as R 3 and R 4 .
• R 1 and R 2 are linked together in a ring
• the bivalent residue R 1 and R 2 represents, in particular: ##STR3## wherein X has the above-indicated values and
• R 5 and R 6 each represent hydrogen, alkyl, alkoxycarbonyl, or alkylaminocarbonyl.
• sugar derivatives utilized in accordance with this process are derived preferably from ribose, deoxyribose, arabinose and glucose.
• Suitable sugar blocking groups are those customary in sugar chemistry, e.g. alkanoyl, benzoyl, p-chlorobenzoyl, p-nitrobenzoyl, p-toluyl, benzyl, etc.
• the nature of the masking group is not critical, since this portion of the molecule is inert with respect to the present reaction.
• the nucleosides to be prepared in accordance with this process contain O-acyl-blocked sugar residues
• the blocking groups of the following acids propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, undecylic acid, oleic acid, pivalic acid, cyclopentylpropionic acid, phenylacetic acid and adamantanecarboxylic acid.
• the free or blocked sugar residue is preferably linked to the nitrogen atom in the manner of a ⁇ -glycoside.
• the process of the present invention is generally applicable for the production of nucleosides.
• Preferred products of the process are nucleosides of the general Formula II ##STR4## wherein R 1 , R 2 , R 3 , R 4 , X and n have the above-indicated values;
• Z is a free or blocked sugar residue
• n is the number 0 or 1.
• nucleosides producible in accordance with this process and, in particular, the products of Formula II are biologically active, as is well known in the art. Depending upon the specific solubility, they can be administered, depending on the choice of the substituent, either systematically as an aqueous or alcoholic solution or locally as an ointment or a jelly.
• the various nucleosides exhibit valuable pharmaceutical properties, depending on the individual compound, e.g. enzyme-inhibiting, antibacterial, antiviral, cytostatic, antipsoriatic and anti-inflammatory activities.
• the reaction of the silylated organic bases, e.g. the bases of Formula Ia or Ib, with a 1-O-acyl, 1-O-alkyl or 1-halogen derivative of a blocked sugar in the presence of the catalyst according to this invention takes place in a suitable inert, preferably aprotic, solvent, e.g. methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, acetonitrile, ethylene chloride, ethylene dichloride, dioxane, tetrahydrofuran, dimethylformamide, carbon disulfide, chlorobenzene, sulfolane, molten dimethylsulfone, etc.
• a suitable inert preferably aprotic, solvent, e.g. methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, acetonitrile, ethylene chloride, ethylene dichloride,
• the reaction can be conducted at room temperature or higher and/or lower temperatures, generally at 0°-100° C., preferably at 0°-20° C.
• the reactants are generally used in the reaction in an approximately equimolar amount, but the silylated heterocyclic is frequently utilized in a minor excess to obtain a maximally quantitative conversion of the sugar component.
• 0.1 equivalent of the catalyst is generally a sufficient catalytic amount but employing equivalent amounts of catalyst permit the reaction to be conducted at the lower temperature of 0°-20°, affording often higher yields of the desired N 1 -nucleoside.
• the catalysts utilized herein have a great advantage over the earlier used Lewis acids or Friedel-Crafts catalysts in that they can be removed immediately and quantitatively simply by shaking with bicarbonate solution, without the formation of emulsions or colloids, because they are at once hydrolyzed to the salt and hexamethyldisiloxane (b.p. 98° C.) which is removed during the evaporation of the solvents.
• the catalysts can be prepared in accordance with methods known from the literature, for example from AgClO 4 with (CH 3 ) 3 SiCl + (CH 3 ) 3 Si--OClO 3 + AgCl as described by U. Wannagat and W. Liehr, "Angew. Chemie” [Applied Chemistry] 69:783 (1957) or, e.g. as in the case of the trimethylsilyl ester of trifluoromethanesulfonic acid, readily from CF 3 SO 3 H and (CH 3 ) 3 SiCl as described by H. C. Marsmann and H. G. Horn in "Z.
• a sugar cation is produced during the reaction as a mineral acid salt, as well as the silylated O-alkyl and O-acyl derivative, respectively.
• the sugar salt reacts with silylated pyrimidine under nucleoside formation and renewed production of silyl ester of the mineral acid, so that catalytic amounts of the silyl ester of the mineral acid are often sufficient; if not, equivalent amounts of catalyst are used to conduct the reaction at lower temperature.
• the yields of the novel reactions are higher than in the processes known heretofore; moreover, primarily ⁇ -derivatives of the sugars are obtained, while the undesired ⁇ -anomers are formed with the exception 2-desoxyribose only in subordinate amounts (less than 1% of the total product) or none at all.
• the new catalysts give rise to much larger amounts of the desired natural N 1 -nucleosides and only limited amounts of the undesired N 3 -nucleosides e.g. in reaction with silylated uracils compared to SnCl 4 as catalyst.
• the blocking groups can then be removed in the usual way, e.g. by means of alcoholic solutions of ammonia or alcoholates, aqueous or alcoholic alkali, as well as, in case of the benzyl ethers, by reduction or hydrogenation.
• Example 1 The procedure of Example 1 was followed, except that only 0.5 mmole of (CH 3 ) 3 SiOClO 3 (in 5 ml. of C 6 H 6 ) was added thereto, and the mixture was refluxed for 4 hours under argon at a bath temperature of 100° C. The reaction mixture was worked up and crystallized, thus obtaining 2.238 g. (80.4%) of uridine-2',3',5'-tri-O-benzoate.
• Example 12 Analogously to Example 12, 5.04 g. (10 mmoles) of 1-O-acetyl-2,3,5-tri-O-benzoyl- ⁇ -D-ribofuranose, 11 mmoles of 1-(trimethylsilyloxy)-1,2,4-triazole, and 12 mmoles of (CH 3 ) 3 SiO--SO 2 CF 3 were reacted with one another and then worked up as set forth in Example 1, yielding 2.94 g. (57.2%) of 1-(1,2,4-triazolyl)- ⁇ -D-ribofuranoside-2',3',5'-tri-O-benzoate, m.p. 105°-106° C.

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Citations (4)

• 1975
  • 1975-02-24 DE DE19752508312 patent/DE2508312A1/de active Granted
• 1976
  • 1976-02-18 NL NL7601625A patent/NL7601625A/xx not_active Application Discontinuation
  • 1976-02-23 SE SE7602109A patent/SE7602109L/xx unknown
  • 1976-02-23 US US05/660,675 patent/US4082911A/en not_active Expired - Lifetime
  • 1976-02-23 GB GB767006A patent/GB1542442A/en not_active Expired
  • 1976-02-23 LU LU74411A patent/LU74411A1/xx unknown
  • 1976-02-23 CA CA246,368A patent/CA1065315A/en not_active Expired
  • 1976-02-24 FR FR7605030A patent/FR2301536A1/fr active Granted
  • 1976-02-24 JP JP51019810A patent/JPS51125382A/ja active Granted
  • 1976-02-24 CH CH227476A patent/CH626093A5/de not_active IP Right Cessation
  • 1976-02-24 DK DK77176A patent/DK138900C/da active
  • 1976-02-24 BE BE164585A patent/BE838879A/xx not_active IP Right Cessation

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